In order to effectively correct genetic disorders in humans, safe and efficient gene delivery systems must be developed, produced in large quantities, purified from contaminants, free of replication competent virus (RCV) and concentrated to high titers. The engineering of effective gene transfer vectors has been a crucial factor for the efficient delivery and expression of therapeutic gene products in vivo. Viruses have been adapted for use as gene transfer vectors taking advantage of natural viral mechanisms designed to efficiently and effectively deliver DMA to the host cell nucleus. Among these, herpes simplex virus type 1 (HSV-1) represents an excellent candidate vector for delivery to the peripheral (PNS) and central nervous systems (CMS) based on the natural biology of the virus that includes the establishment of a life-long latent state in neurons in which the viral genome persists as an episomal molecule. Considerable effort in the development of HSV-1 vectors has resulted in the engineering of totally replication defective vectors that are non-toxic for neurons and are capable of long-term transgene expression in neurons of the PNS. As well, efforts in process development have resulted in scaleable systems capable of manufacturing these vectors for pre-clinical efficacy and safety testing. The primary goal of the Pre-Clinical Vector Core will be to provide large quantities of concentrated and purified HSV-1 vectors expressing single or multiple therapeutic genes to each of the projects for the proposed experiments. The Pre-Clinical Vector Core will work with the projects to provide optimal vector quantity and purity. The proposed design of the Pre-Clinical Vector Core will be to provide the support necessary to successfully exploit the available technology. The specific aims of the Pre-Clinical Vector Core are: (1) to provide each investigator with the appropriate purified HSV-1 vector already in-hand expressing the required therapeutic or marker gene to successfully complete the proposed pre-clinical experiments;and (2) to provide technical assistance, reagents, and protocols to each of the projects including the development of new or modified protocols for the production and purification of HSV vectors for pre-clinical experiments. Should success in these projects lead to the initiation of Phase-l human clinical trials, the Pre-Clinical Vector Core is set up to transition the production of these vectors to the Human Gene Therapy Applications Laboratory (HGTAL) as part of the University of Pittsburgh Molecular Medicine Institute (MMI).